Bottom Line:
However, the absolute number of NK1(+) T cells in the thymus of IL-7Ralpha-deficient mice is reduced to approximately 10%, compared to natural T cell number in the wild-type thymus.Additional data revealed that NK1(+) T cell ontogeny is not impaired in IL-2- or IL-4-deficient mice, suggesting that neither IL-2, IL-4, nor IL-7 are required for their development.From these data, we conclude that commitment and/or differentiation to the NK1(+) natural T cell lineage requires signal transduction through the gammac, and once committed, their expansion requires signals relayed through the IL-7Ralpha.

Affiliation: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA.

ABSTRACTThe commitment, differentiation, and expansion of mainstream alpha/beta T cells during ontogeny depend on the highly controlled interplay of signals relayed by cytokines through their receptors on progenitor cells. The role of cytokines in the development of natural killer (NK)1(+) natural T cells is less clearly understood. In an approach to define the role of cytokines in the commitment, differentiation, and expansion of NK1(+) T cells, their development was studied in common cytokine receptor gamma chain (gammac) and interleukin (IL)-7 receptor alpha (IL-7Ralpha)-deficient mice. These mutations block mainstream alpha/beta T cell ontogeny at an early prethymocyte stage. Natural T cells do not develop in gammac-deficient mice; they are absent in the thymus and peripheral lymphoid organs such as the liver and the spleen. In contrast, NK1(+) T cells develop in IL-7Ralpha-deficient mice in the thymus, and they are present in the liver and in the spleen. However, the absolute number of NK1(+) T cells in the thymus of IL-7Ralpha-deficient mice is reduced to approximately 10%, compared to natural T cell number in the wild-type thymus. Additional data revealed that NK1(+) T cell ontogeny is not impaired in IL-2- or IL-4-deficient mice, suggesting that neither IL-2, IL-4, nor IL-7 are required for their development. From these data, we conclude that commitment and/or differentiation to the NK1(+) natural T cell lineage requires signal transduction through the gammac, and once committed, their expansion requires signals relayed through the IL-7Ralpha.

Figure 2: IL-2–, IL-4–, and IL-7Rα–deficient mice develop thymic NTα/β T cells. (A) Dot plots of CD44highNKR-P1+, CD44highTCR-α/βmed, and CD44highTCR-β8.1,8.2med T cells among HSAlowCD8low thymocytes of B6.IL-20/0 (n = 5), B6.IL-40/0 (n = 6) and B6.IL-7Rα0/0 mice (n = 6). (B) Dot plots of Ly6ChighNKR-P1+ T cells among HSAlowCD8low thymocytes. (C) Dot plots of IL-2 Rβ+NKR-P1+ (B6.IL-40/0 and B6.IL-7Rα0/0) and of IL-2Rβ+TCR-α/β+ (B6.IL-20/0 and B6.IL-7Rα0/0) T cells among HSAlowCD8low thymocytes. In B and C, the percentage of NT cells was almost equal in B6.IL-40/0, about half in B6.IL-7Rα0/0, or up to twofold greater in B6.IL-20/0 compared with those in the wild type. (D) Absolute numbers of HSAlowCD8low thymocytes calculated as the thymocyte number times the fraction of this subset. (E) Thymic NT cells in wild-type, IL-20/0, IL-40/0 and IL-7Rα0/0 mice. NT cell number was calculated from the percentages of the double-positive CD44+ and NKR-P1+, TCR-α/β+ or Vβ8.1,8.2+ thymocytes within the electronically gated HSAlowCD8low population in D as described previously (5).

Mentions:
γc serves as an essential component of the multimeric receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 (18). To determine which of the cytokines that use γc receptor affect NT cell development, the thymi of >6-wk-old B6.IL-20/0, B6.IL-40/0 and B6.IL-7Rα0/0 mice were analyzed. Mainstream T lymphocyte development is impaired in B6.IL-7 Rα0/0 mice, but proceeds normally in B6.IL-20/0 (19) and B6.IL-40/0 (20) mice. All three mutant mice develop CD44highNKR-P1+ T cells (Fig. 2 A). The repertoire of α/β-TCR is skewed towards Vβ8.1,8.2 usage in >40% (the percentage of TCR-α/β+ thymocytes that are Vβ8.1, 8.2+) of these NT cells (Fig. 2 A). Further data revealed that the NT cells that develop in B6.IL-40/0 and B6.IL-7 Rα0/0 mice also express Ly6C (Fig. 2 B) and that all the three mutant mice express IL-2Rβ (Fig. 2 C) similar to the NK1+ T cells that develop in the wild-type C57BL/6 mice. These data suggest that neither IL-2, IL-4, IL-7, nor thymic stromal-derived lymphopoietin (TSLP; IL-7Rα is a receptor component of IL-7 and TSLP; 16) are required for NT cell ontogeny.

Figure 2: IL-2–, IL-4–, and IL-7Rα–deficient mice develop thymic NTα/β T cells. (A) Dot plots of CD44highNKR-P1+, CD44highTCR-α/βmed, and CD44highTCR-β8.1,8.2med T cells among HSAlowCD8low thymocytes of B6.IL-20/0 (n = 5), B6.IL-40/0 (n = 6) and B6.IL-7Rα0/0 mice (n = 6). (B) Dot plots of Ly6ChighNKR-P1+ T cells among HSAlowCD8low thymocytes. (C) Dot plots of IL-2 Rβ+NKR-P1+ (B6.IL-40/0 and B6.IL-7Rα0/0) and of IL-2Rβ+TCR-α/β+ (B6.IL-20/0 and B6.IL-7Rα0/0) T cells among HSAlowCD8low thymocytes. In B and C, the percentage of NT cells was almost equal in B6.IL-40/0, about half in B6.IL-7Rα0/0, or up to twofold greater in B6.IL-20/0 compared with those in the wild type. (D) Absolute numbers of HSAlowCD8low thymocytes calculated as the thymocyte number times the fraction of this subset. (E) Thymic NT cells in wild-type, IL-20/0, IL-40/0 and IL-7Rα0/0 mice. NT cell number was calculated from the percentages of the double-positive CD44+ and NKR-P1+, TCR-α/β+ or Vβ8.1,8.2+ thymocytes within the electronically gated HSAlowCD8low population in D as described previously (5).

Mentions:
γc serves as an essential component of the multimeric receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 (18). To determine which of the cytokines that use γc receptor affect NT cell development, the thymi of >6-wk-old B6.IL-20/0, B6.IL-40/0 and B6.IL-7Rα0/0 mice were analyzed. Mainstream T lymphocyte development is impaired in B6.IL-7 Rα0/0 mice, but proceeds normally in B6.IL-20/0 (19) and B6.IL-40/0 (20) mice. All three mutant mice develop CD44highNKR-P1+ T cells (Fig. 2 A). The repertoire of α/β-TCR is skewed towards Vβ8.1,8.2 usage in >40% (the percentage of TCR-α/β+ thymocytes that are Vβ8.1, 8.2+) of these NT cells (Fig. 2 A). Further data revealed that the NT cells that develop in B6.IL-40/0 and B6.IL-7 Rα0/0 mice also express Ly6C (Fig. 2 B) and that all the three mutant mice express IL-2Rβ (Fig. 2 C) similar to the NK1+ T cells that develop in the wild-type C57BL/6 mice. These data suggest that neither IL-2, IL-4, IL-7, nor thymic stromal-derived lymphopoietin (TSLP; IL-7Rα is a receptor component of IL-7 and TSLP; 16) are required for NT cell ontogeny.

Bottom Line:
However, the absolute number of NK1(+) T cells in the thymus of IL-7Ralpha-deficient mice is reduced to approximately 10%, compared to natural T cell number in the wild-type thymus.Additional data revealed that NK1(+) T cell ontogeny is not impaired in IL-2- or IL-4-deficient mice, suggesting that neither IL-2, IL-4, nor IL-7 are required for their development.From these data, we conclude that commitment and/or differentiation to the NK1(+) natural T cell lineage requires signal transduction through the gammac, and once committed, their expansion requires signals relayed through the IL-7Ralpha.

Affiliation:
Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA.

ABSTRACTThe commitment, differentiation, and expansion of mainstream alpha/beta T cells during ontogeny depend on the highly controlled interplay of signals relayed by cytokines through their receptors on progenitor cells. The role of cytokines in the development of natural killer (NK)1(+) natural T cells is less clearly understood. In an approach to define the role of cytokines in the commitment, differentiation, and expansion of NK1(+) T cells, their development was studied in common cytokine receptor gamma chain (gammac) and interleukin (IL)-7 receptor alpha (IL-7Ralpha)-deficient mice. These mutations block mainstream alpha/beta T cell ontogeny at an early prethymocyte stage. Natural T cells do not develop in gammac-deficient mice; they are absent in the thymus and peripheral lymphoid organs such as the liver and the spleen. In contrast, NK1(+) T cells develop in IL-7Ralpha-deficient mice in the thymus, and they are present in the liver and in the spleen. However, the absolute number of NK1(+) T cells in the thymus of IL-7Ralpha-deficient mice is reduced to approximately 10%, compared to natural T cell number in the wild-type thymus. Additional data revealed that NK1(+) T cell ontogeny is not impaired in IL-2- or IL-4-deficient mice, suggesting that neither IL-2, IL-4, nor IL-7 are required for their development. From these data, we conclude that commitment and/or differentiation to the NK1(+) natural T cell lineage requires signal transduction through the gammac, and once committed, their expansion requires signals relayed through the IL-7Ralpha.